Virtual Screening for Inhibitors of the Human TSLP:TSLPR Interaction

Overview

Journal Sci Rep

Specialty Science

Date 2017 Dec 10

PMID 29222519

Citations 6

Authors

Dries Van Rompaey

Kenneth Verstraete

Frank Peelman

Savvas N Savvides

Koen Augustyns

Pieter Van der Veken

Hans De Winter

Affiliations

Soon will be listed here.

Abstract

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Rα), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP:TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP:alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP:TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-of-principle for use of fragments in the inhibition of TSLP:TSLPR complexation.

Citing Articles

Disrupting TSLP-TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases.

Adhikary P, Idowu T, Tan Z, Hoang C, Shanta S, Dumbani M EMBO Mol Med. 2024; 16(7):1630-1656.

PMID: 38877290 PMC: 11250841. DOI: 10.1038/s44321-024-00085-3.

Alterations in Acute Lymphoblastic Leukemia: Molecular Insights for Superior Precision Medicine Strategies.

Downes C, McClure B, McDougal D, Heatley S, Bruning J, Thomas D Front Cell Dev Biol. 2022; 10:942053.

PMID: 35903543 PMC: 9315936. DOI: 10.3389/fcell.2022.942053.

TSLP disease-associated genetic variants combined with airway TSLP expression influence asthma risk.

Murrison L, Ren X, Preusse K, He H, Kroner J, Chen X J Allergy Clin Immunol. 2021; 149(1):79-88.

PMID: 34111451 PMC: 9119142. DOI: 10.1016/j.jaci.2021.05.033.

Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer.

Markovic I, Savvides S Front Immunol. 2020; 11:1557.

PMID: 32849527 PMC: 7396566. DOI: 10.3389/fimmu.2020.01557.

TSLP Inhibitors for Asthma: Current Status and Future Prospects.

Matera M, Rogliani P, Calzetta L, Cazzola M Drugs. 2020; 80(5):449-458.

PMID: 32078149 DOI: 10.1007/s40265-020-01273-4.

References

Guillot-Delost M, Guillere L, Berger F, Ventre A, Michea P, Sirven P . Ligand-receptor dissociated expression explains high TSLP without prognostic impact in human primary head and neck squamous cell carcinoma. Oncoimmunology. 2016; 5(7):e1179414. PMC: 5006899. DOI: 10.1080/2162402X.2016.1179414. View

Deng L, Zhang Q, Chen Z, Meng Y, Guan J, Zhou S . PredHS: a web server for predicting protein-protein interaction hot spots by using structural neighborhood properties. Nucleic Acids Res. 2014; 42(Web Server issue):W290-5. PMC: 4086081. DOI: 10.1093/nar/gku437. View

Prinz J, Wu H, Sarich M, Keller B, Senne M, Held M . Markov models of molecular kinetics: generation and validation. J Chem Phys. 2011; 134(17):174105. DOI: 10.1063/1.3565032. View

Di Piazza M, Nowell C, Koch U, Durham A, Radtke F . Loss of cutaneous TSLP-dependent immune responses skews the balance of inflammation from tumor protective to tumor promoting. Cancer Cell. 2012; 22(4):479-93. DOI: 10.1016/j.ccr.2012.08.016. View

Braisted A, Oslob J, DeLano W, Hyde J, McDowell R, Waal N . Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. J Am Chem Soc. 2003; 125(13):3714-5. DOI: 10.1021/ja034247i. View

Joseph-McCarthy D, Campbell A, Kern G, Moustakas D . Fragment-based lead discovery and design. J Chem Inf Model. 2014; 54(3):693-704. DOI: 10.1021/ci400731w. View

Demehri S, Turkoz A, Manivasagam S, Yockey L, Turkoz M, Kopan R . Elevated epidermal thymic stromal lymphopoietin levels establish an antitumor environment in the skin. Cancer Cell. 2012; 22(4):494-505. PMC: 3480666. DOI: 10.1016/j.ccr.2012.08.017. View

Storz U . Intellectual property protection: strategies for antibody inventions. MAbs. 2011; 3(3):310-7. PMC: 3149711. DOI: 10.4161/mabs.3.3.15530. View

Yin J, Zhao M, Huffman M, McNamara J . Pd-catalyzed N-arylation of heteroarylamines. Org Lett. 2002; 4(20):3481-4. DOI: 10.1021/ol0265923. View

10.

Doerr S, Harvey M, Noe F, De Fabritiis G . HTMD: High-Throughput Molecular Dynamics for Molecular Discovery. J Chem Theory Comput. 2016; 12(4):1845-52. DOI: 10.1021/acs.jctc.6b00049. View

11.

Corren J, Parnes J, Wang L, Mo M, Roseti S, Griffiths J . Tezepelumab in Adults with Uncontrolled Asthma. N Engl J Med. 2017; 377(10):936-946. DOI: 10.1056/NEJMoa1704064. View

12.

Levin S, Koelling R, Friend S, Isaksen D, Ziegler S, Perlmutter R . Thymic stromal lymphopoietin: a cytokine that promotes the development of IgM+ B cells in vitro and signals via a novel mechanism. J Immunol. 1999; 162(2):677-83. View

13.

Bogan A, Thorn K . Anatomy of hot spots in protein interfaces. J Mol Biol. 1998; 280(1):1-9. DOI: 10.1006/jmbi.1998.1843. View

14.

Park L, Martin U, Garka K, Gliniak B, Di Santo J, Muller W . Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptor. J Exp Med. 2000; 192(5):659-70. PMC: 2193276. DOI: 10.1084/jem.192.5.659. View

15.

Wang J, Wolf R, Caldwell J, Kollman P, Case D . Development and testing of a general amber force field. J Comput Chem. 2004; 25(9):1157-74. DOI: 10.1002/jcc.20035. View

16.

Sun D, Li Z, Rew Y, Gribble M, Bartberger M, Beck H . Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. 2014; 57(4):1454-72. DOI: 10.1021/jm401753e. View

17.

Gauvreau G, OByrne P, Boulet L, Wang Y, Cockcroft D, Bigler J . Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014; 370(22):2102-10. DOI: 10.1056/NEJMoa1402895. View

18.

Noti M, Tait Wojno E, Kim B, Siracusa M, Giacomin P, Nair M . Thymic stromal lymphopoietin-elicited basophil responses promote eosinophilic esophagitis. Nat Med. 2013; 19(8):1005-13. PMC: 3951204. DOI: 10.1038/nm.3281. View

19.

Hall D, Ngan C, Zerbe B, Kozakov D, Vajda S . Hot spot analysis for driving the development of hits into leads in fragment-based drug discovery. J Chem Inf Model. 2011; 52(1):199-209. PMC: 3264775. DOI: 10.1021/ci200468p. View

20.

Souers A, Leverson J, Boghaert E, Ackler S, Catron N, Chen J . ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013; 19(2):202-8. DOI: 10.1038/nm.3048. View